Barbara A Hutten

Netherlands Bioinformatics Centre, Nymegen, Gelderland, Netherlands

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Publications (163)1145.55 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Venous thromboembolism (VTE), including pulmonary embolism (PE) is often accompanied by stress-hyperglycemia. Vice versa, there is evidence that hyperglycemia contributes to coagulation activation and hypofibrinolysis, resulting in a pro-thrombotic state.
    11/2015; 10(3):145-146. DOI:10.1007/s12467-012-0100-5
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    ABSTRACT: Fibroblast growth factor 21 (FGF21) has been described to have beneficial effects on glucose and lipid metabolism, and FGF21 analogs are currently evaluated in phase 1 trials. However, the complete spectrum of effects and regulators of FGF21 is yet partly elucidated. Recent studies have shown that FGF21 plays a role in transmembrane cholesterol transport. We set out to examine the association between FGF21 and LDLR mediated transmembrane cholesterol transport, by comparing FGF21 levels in patients with genetically impaired LDLR function and unaffected relatives. Secondly, we explored whether the severity of the LDLR mutation was associated with FGF21 levels. We performed a cross-sectional study in carriers of an LDLR mutation and their unaffected relatives. Subjects were eligible if they participated in the Dutch national screening program for familial hypercholesterolemia (FH), were 18-55 years old, and were carrier of a pathogenic LDLR mutation with an untreated LDL-C level below the 75(th) or above the 90(th) percentile of the general population, or did not carry an FH mutation. The outcome measure was the level of FGF21, which was assessed using ELISA. We included 224 carriers of an LDLR mutation and 148 unaffected relatives. FGF21 levels were lower in LDLR mutation carriers compared to unaffected relatives (median [interquartile range]: 96.92 [60.80-174.05] versus 136.98 [77.34-219.47] pg/mL, respectively; p = 0.08), but after adjusting for potential confounders, there was no association between LDLR mutations and FGF21 levels (p = 0.70). Neither, did we find a relationship between the severity of LDLR mutations and FGF21 levels (p = 0.51, after adjustment for potential confounders). We showed that levels of FGF21 are not different in patients with and without LDLR mutations, which suggests that decreased LDLR expression does not have a negative effect on FGF21 levels. Given the potential beneficial effects of FGF21 analogs on lipids and lipoproteins in a phase 1 study, we deem this of great interest for future treatment options for FH patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 08/2015; 241(2). DOI:10.1016/j.atherosclerosis.2015.05.032 · 3.97 Impact Factor
  • Saskia Middeldorp, Barbara A Hutten
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    ABSTRACT: Is long-term (≥3 months) vs short-term therapy with vitamin K antagonists (VKAs) associated with differences in the incidence of recurrent venous thromboembolism (VTE), major bleeding, and mortality in patients with symptomatic VTE? Long-term treatment with VKAs is associated with a reduced risk for recurrent VTE and an increased risk for major bleeding compared with short-term treatment in patients with VTE, but is not associated with differences in mortality.
    JAMA The Journal of the American Medical Association 07/2015; 314(1):72-73. DOI:10.1001/jama.2015.2693 · 30.39 Impact Factor
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    ABSTRACT: Statins are currently the preferred pharmacological therapy in children with familial hypercholesterolemia (FH) with the aim to prevent premature cardiovascular disease (CVD). However, concerns have been raised that lowering cholesterol levels with statins could interfere with hormone production. In this study hormone concentrations were assessed in young adult FH subjects before and 10 years after the initiation of statins, and compared with their unaffected siblings. All 214 FH children (8-18 years) who were previously randomized into a placebo-controlled trial evaluating the 2-year efficacy and safety of pravastatin, and their 95 unaffected siblings, were eligible. Women using oral contraceptives were excluded. Fasted blood samples were taken to measure lipids and testosterone (males), estradiol (females), luteinizing hormone (LH), follicle-stimulating hormone (FSH) and dehydroepiandosterone (DHEAS). After ten years, gonadal steroid and gonadotropin concentrations were within the reference interval and did not differ between FH subjects (n = 88) and unaffected siblings (n = 62). Mean DHEAS concentrations (±standard deviation) in the FH subjects and female siblings were normally distributed within the reference interval, whereas male siblings had a higher mean DHEAS concentration than their FH brothers (12.9 [± 4.9] vs. 8.4 [± 3.0] μmol/L, respectively, p < 0.0001). After ten years of statin treatment, testosterone, estradiol, LH and FSH concentrations in young adult FH patients are within the reference interval and comparable to their unaffected siblings. These results strengthen current guidelines that statins in FH subjects could be safely used from childhood onwards to prevent premature CVD. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 06/2015; 241(2). DOI:10.1016/j.atherosclerosis.2015.05.034 · 3.97 Impact Factor
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    ABSTRACT: This article provides recent insights on the early onset of atherosclerosis in heterozygous familial hypercholesterolemia and reports on novel treatment options as well as on the consequences of long-term statin use in childhood. Children with familial hypercholesterolemia have greater mean carotid intima-media thickness (cIMT) than their unaffected siblings even before the age of 8 years, which is several years earlier than previously reported. In those children, 2 years of rosuvastatin treatment resulted in slowing of the cIMT progression. In addition, in a 10-year follow-up study after a pravastatin intervention trial, long-term statin therapy in young adult familial hypercholesterolemia patients was associated with normalization of cIMT progression and appeared effective in prevention of very premature cardiovascular events. These effects were observed without untoward safety concerns. However, a majority of these young adults did not reach cholesterol goals according to general guidelines, indicating the need for improvement of treatment in this patient group. The importance, efficacy and safety of early initiation statin therapy in familial hypercholesterolemia children were further confirmed by recent findings. Nevertheless, to reach current treatment goals, the use of more potent statins is required and has been proven well tolerated and effective in young children.
    Current opinion in lipidology 06/2015; 26(3):236-9. DOI:10.1097/MOL.0000000000000177 · 5.80 Impact Factor
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    ABSTRACT: A large number of studies have shown an association between inherited thrombophilia and recurrent miscarriage. It has been hypothesized that anticoagulant therapy might reduce the number of miscarriages and stillbirth in these women. In the absence of randomized controlled trials evaluating the efficacy of anticoagulant therapy in women with inherited thrombophilia and recurrent miscarriage, a randomized trial with adequate power that addresses this question is needed. The objective of the ALIFE2 study is therefore to evaluate the efficacy of low-molecular-weight heparin (LMWH) in women with inherited thrombophilia and recurrent miscarriage, with live birth as the primary outcome. Randomized study of LMWH plus standard pregnancy surveillance versus standard pregnancy surveillance alone. pregnant women of less than 7 weeks' gestation, and confirmed inherited thrombophilia with a history of 2 or more miscarriages or intra-uterine fetal deaths, or both. multi-center study in centers from the Dutch Consortium of Fertility studies; centers outside the Netherlands are currently preparing to participate. LMWH enoxaparin 40 mg subcutaneously once daily started prior to 7 weeks gestational age plus standard pregnancy surveillance or standard pregnancy surveillance alone. Main study parameters/endpoints: the primary efficacy outcome is live birth. Secondary efficacy outcomes include adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, syndrome of hemolysis, elevated liver enzymes and low platelets (HELLP syndrome), fetal growth restriction, placental abruption, premature delivery and congenital malformations. Safety outcomes include bleeding episodes, thrombocytopenia and skin reactions. After an initial period of slow recruitment, the recruitment rate for the study has increased. Improved awareness of the study and acknowledgement of the need for evidence are thought to be contributing to the improved recruitment rates. We aim to increase the number of recruiting centers in order to increase enrollment into the ALIFE2 study. The study website can be accessed via www.ALIFE2study.org . The ALIFE2 study was registered on 19 March 2012 under registration number NTR3361.
    Trials 05/2015; 16(1):208. DOI:10.1186/s13063-015-0719-9 · 2.12 Impact Factor
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    ABSTRACT: Intensive glucose control, often involving insulin treatment, failed to improve cardiovascular outcomes in several clinical trials. Observational studies reported an association between insulin use and cardiovascular disease (CVD) risk. It has therefore been suggested that insulin adversely affects CVD risk. To investigate the feasibility of this hypothesis, we studied the association between insulin dose and CVD risk in type 2 diabetes. A case-control study was conducted of new users of oral antidiabetics who were prescribed insulin, using the Dutch Pharmo database. Cases were hospitalized for a cardiovascular event (CVE) and matched 1:2 to patients who were not hospitalized for a CVE, by sex, age, duration of diabetes and type of oral antidiabetic. Patients were divided into tertiles according to mean daily insulin dose. Conditional logistic regression analyses were used to explore the association between insulin exposure and CVE risk. We included 836 patients (517 (62%) male, mean age 66 years). After adjusting for available potential confounders, including HbA1c and triglycerides, insulin exposure was positively related to CVE risk (odds ratios for high (≥53.0 U/day) and intermediate (24.3-52.9 U/day) vs. low exposure (≤24.2 U/day): 3.00 [95% confidence interval (CI) 1.70 to 5.28] and 2.03 [95% CI 1.17 to 3.52]. Our findings are in line with the suggestion that high-dose insulin therapy adversely affects CVD risk, but need to be interpreted with caution due to the observational nature of the study. The role of particularly high-dose insulin in the progression of CVD warrants further investigation. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
    Atherosclerosis 03/2015; 240(2):318-323. DOI:10.1016/j.atherosclerosis.2015.03.040 · 3.97 Impact Factor
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    ABSTRACT: Familial hypercholesterolemia is characterized by impaired uptake of cholesterol in peripheral tissues, including the liver and the pancreas. In contrast, statins increase the cellular cholesterol uptake and are associated with increased risk for type 2 diabetes mellitus. We hypothesize that transmembrane cholesterol transport is linked to the development of type 2 diabetes. To assess the association between type 2 diabetes prevalence and familial hypercholesterolemia. Cross-sectional study in all individuals (n = 63 320) who underwent DNA testing for familial hypercholesterolemia in the national Dutch screening program between 1994 and 2014. Deleteriousness and nondeleteriousness of familial hypercholesterolemia mutations were based on literature or laboratory function testing. Low-density lipoprotein (LDL) receptor mutations were considered more severe than apolipoprotein B gene (APOB) mutations, and receptor-negative LDL receptor mutations were considered more severe than receptor-deficient mutations. Prevalence of type 2 diabetes. The prevalence of type 2 diabetes was 1.75% in familial hypercholesterolemia patients (n = 440/25 137) vs 2.93% in unaffected relatives (n = 1119/38 183) (P < .001; odds ratio [OR], 0.62 [95% CI, 0.55-0.69]). The adjusted prevalence of type 2 diabetes in familial hypercholesterolemia, determined using multivariable regression models, was 1.44% (difference, 1.49% [95% CI, 1.24%-1.71%]) (OR, 0.49 [95% CI, 0.41-0.58]; P < .001). The adjusted prevalence of type 2 diabetes by APOB vs LDL receptor gene was 1.91% vs 1.33% (OR, 0.65 [95% CI, 0.48-0.87] vs OR, 0.45 [95% CI, 0.38-0.54]), and the prevalence for receptor-deficient vs receptor-negative mutation carriers was 1.44% vs 1.12% (OR, 0.49 [95% CI, 0.40-0.60] vs OR, 0.38 [95% CI, 0.29-0.49]), respectively (P for trend <.001 in both comparisons). In a cross-sectional analysis in the Netherlands, the prevalence of type 2 diabetes among patients with familial hypercholesterolemia was significantly lower than among unaffected relatives, with variability by mutation type. If this finding is confirmed in longitudinal analysis, it would raise the possibility of a causal relationship between LDL receptor-mediated transmembrane cholesterol transport and type 2 diabetes.
    JAMA The Journal of the American Medical Association 03/2015; 313(10):1029-1036. DOI:10.1001/jama.2015.1206 · 30.39 Impact Factor
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    ABSTRACT: Background Statins are currently the preferred pharmacological therapy in individuals with familial hypercholesterolemia (FH) with the aim to prevent premature atherosclerosis. In adults, these agents have been proven to be safe and well tolerated; however, non-adherence is a significant clinical issue. Objectives In this study, we evaluated tolerability and adherence to statin therapy in young adult FH patients 10 years after this was initiated in their childhood. Methods A questionnaire including items on medical history, adherence and reasons for discontinuation was sent to 214 young adult FH patients that initiated statin therapy at least 10 years ago. Tolerability was defined as 100 % minus the percentage of patients that discontinued statin therapy due to side effects. Adherence was defined as the extent to which patients took their medication as prescribed by their physician. We labelled patients adherent if they took 80 % or more of their pills in the month preceding our assessment. Results Follow-up was successful in 205 (95.8 %) subjects (age 18–30 years). A history of side effects was reported by 40 (19.5 %) of the patients, and mainly consisted of muscle complaints and gastrointestinal symptoms. Three patients (1.5 %) discontinued statin therapy because of side effects. Rhadbomyolysis or other serious adverse events were not reported. In fact, 169 (82.4 %) of 205 patients remained on statin treatment and 78.7 % (148 out of 188) were adherent. None of the patient characteristics were significantly associated with adherence. Conclusions Individuals with FH who started statin therapy in childhood demonstrated good adherence during ten years of treatment. Furthermore, statin therapy was well tolerated; only a small minority discontinued therapy because of side effects and the side effects that were reported were mild in nature.
    Paediatric Drugs 02/2015; 17(2). DOI:10.1007/s40272-014-0116-y · 1.72 Impact Factor
  • Sigrid W Fouchier, Barbara A Hutten, Joep C Defesche
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    ABSTRACT: Autosomal-dominant hypercholesterolaemia (ADH) is a heterogeneous common disorder, and uncovering the molecular determinants that underlie ADH is a major focus of cardiovascular research. However, despite rapid technical advances, efforts to identify novel ADH genes have yet not been very successful and are largely challenged by phenotypic and genetic heterogeneity of this disease. We aimed to investigate the impact of this phenotypic heterogeneity on successfully finding new genes that are involved in ADH. For the ADH phenotype, subjects are considered as affected according to plasma cholesterol levels above the 95th percentile for age and gender. The disease penetrance is generally set at 0.9. These parameters were evaluated in 10 000 carriers of true pathogenic APOB and LDLR mutations and 20 000 relatives negative for the familial mutations. Application of the above parameters in almost a thousand families included in this study would have identified the causal variant in only 38% of all families. An average penetrance of 0.9 or higher, with a cut-point at the 95th percentile, was only observed for LDLR nonsense mutations. For APOB and LDLR missense mutations, a disease penetrance of 0.9 or higher is only expected, when total cholesterol and low-density lipoprotein cholesterol cut-points between the 75th and 90th percentile are used to determine an individual's disease status. Although pathogenic LDLR and APOB mutations do follow Mendelian patterns of inheritance, the extensive variation in genotype and phenotype for well-known ADH-causing mutations emphasises that current criteria and strategies indeed are likely to hamper the identification of novel genes related to ADH. These findings provide a basis for the revision of our assessment on who is affected and who is not and emphasise the essence of pedigree information and mapping data before exome sequencing is applied in order to increase success rates of finding new genes related to ADH. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    Journal of Medical Genetics 11/2014; 52(2). DOI:10.1136/jmedgenet-2014-102653 · 5.64 Impact Factor
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    ABSTRACT: Since 2004, guidelines recommend long-term treatment with low-molecular-weight heparin (LMWH) in patients with cancer and pulmonary embolism (PE). We assessed the proportion of cancer patients with PE actually treated with LMWH and the duration of anticoagulant treatment in the Netherlands. A retrospective cohort study in patients that were hospitalised for PE between 1998-2008. Patients with PE were selected from national hospital discharge records, after linkage to a national pharmacy database. Cancer patients with PE were matched for age, sex and year of diagnosis of PE to subjects with PE without cancer. 600 cancer patients with PE were matched to 1200 patients with PE without cancer. Long-term LMWH was prescribed in 82 (13.7%) of the cancer patients and in eight (0.7%) of the cancer-free patients (p < 0.001); all the other patients received vitamin K antagonists (VKA). From 1998-2008, there was an increase in the use of LMWH in cancer patients: in 2007-2008, LMWH was prescribed in 42 (32%) cases, compared with one (1.7%) of the cancer patients with PE in 1998-1999. Median duration of treatment was 5.8 months (interquartile range 3.1-8.8) in cancer patients, compared with 7.0 months (4.9-11) in patients without cancer (p < 0.001), a difference that persisted after adjustment for mortality. Although the use of LMWH in patients with cancer and PE is increasing, in 2008, patients in the Netherlands are still mostly treated with VKA, and not with LMWH as recommended by guidelines. Cancer patients with PE on average receive shorter treatment than matched patients without cancer.
    The Netherlands Journal of Medicine 11/2014; 72(9):467-73. · 2.21 Impact Factor
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    JAMA The Journal of the American Medical Association 09/2014; 312(10):1055-1057. DOI:10.1001/jama.2014.8892 · 30.39 Impact Factor
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    ABSTRACT: Introduction: Homozygous familial hypercholesterolemia (HoFH) is a rare disorder characterized by severely increased cholesterol levels that lead to an extremely high risk of premature cardiovascular disease (CVD). Aggressive lipid-lowering therapy should be started at an early age with highly potent statins. Rosuvastatin is such a highly efficacious statin with a favorable safety profile that might be advantageous in pediatric HoFH.Areas covered: The authors conducted a PubMed search for rosuvastatin papers and papers on statin use in HoFH published in English. This review describes the pharmacology, safety and efficacy of rosuvastatin and discusses its use in pediatric HoFH.Expert opinion: To date, there is very little evidence on the efficacy and safety of rosuvastatin in pediatric HoFH. Sufficient clinical evidence has proven the lipid-lowering capacity and subsequent CVD prevention of rosuvastatin in hypercholesterolemic adults. Furthermore, clinical studies in children heterozygous familial hypercholesterolemia aged 6 years and older revealed no untoward safety concerns. Rosuvastatin is, therefore, a promising agent in the treatment of pediatric HoFH.
    09/2014; DOI:10.1517/21678707.2014.958467
  • Fertility and Sterility 09/2014; 102(3):e82. DOI:10.1016/j.fertnstert.2014.07.279 · 4.59 Impact Factor
  • Atherosclerosis 08/2014; 235(2):e15. DOI:10.1016/j.atherosclerosis.2014.05.013 · 3.97 Impact Factor
  • Journal of the American College of Cardiology 04/2014; 63(12):A334. DOI:10.1016/S0735-1097(14)60334-X · 15.34 Impact Factor
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    ABSTRACT: What is the time to conception in a cohort of women with unexplained recurrent miscarriage (RM). Median time to conception in women diagnosed with unexplained RM was 21 weeks (interquartile range (IQR) 8-55 weeks), with a cumulative incidence of conception of 74% after 12 months of trying to conceive. There is no effective treatment in couples with unexplained RM. Adequate counselling about their prognosis, for example time to conception and time to a live birth, is therefore very important. So far, there are no studies that give insight on these issues. A nested prospective cohort study was performed from February 2004 through July 2009 within a multicentre randomized placebo-controlled trial (ALIFE trial) on anticoagulant treatment in 364 women with unexplained RM. A total of 251 women who were not pregnant at the time of diagnosis of unexplained RM were included in this study. Of these, 13% became pregnant with ART, and all other women conceived naturally. The primary outcome was time to conception in weeks, calculated from the moment of diagnosis until conception measured by a urinary HCG. Secondary outcome was time to a live birth in the subsequent pregnancy. The relative prognostic significance of female age, the number of preceding miscarriages, interventions within the trial and the presence or absence of a preceding late miscarriage, a previous live birth and factor V Leiden mutation, was evaluated by Cox regression for time to conception and by competing risk modelling for time to live birth, respectively. The cumulative incidence of conception was 56% after 6 months, 74% after 12 months and 86% after 24 months of which 65% resulted in a live birth. The median time to conception was 21 weeks (IQR 8-55 weeks). Of potential prognostic factors, the presence of the factor V Leiden mutation resulted in a significantly shorter median time to conception of 11 weeks for carriers versus 23 weeks for non-carriers (hazard ratio (HR) 1.94, 95% confidence interval (CI) 1.03-3.65). The cumulative incidence of a live birth of the subsequent pregnancy was 0% after 6 months, 23% after 12 months and 50% after 24 months. The median time to a live birth of the subsequent pregnancy was 102 weeks (IQR 82-115 weeks). The number of previous miscarriages was the only prognostic factor (HR 0.83, 95% CI 0.74-0.94) significantly associated with time to a live birth of the subsequent pregnancy. In our study only the subsequent pregnancy after diagnosing unexplained RM was included. A future collection of cumulative follow-up data of all the women included in this cohort may provide outcomes of all pregnancies following the diagnosis of unexplained RM. Time to conception in women diagnosed with unexplained RM appears to be comparable with time to conception in healthy fertile women, as reported in the literature. The interesting finding that women with Factor V Leiden mutation have a significant shorter time to conception may suggest a favourable embryo implantation process. Future research is needed to confirm these findings and unravel the biology of early implantation. The RCT used for this nested cohort study was funded by a grant (945-27-003) from the Netherlands Organization for Health Research and Development and a grant from GlaxoSmithKline. Study drugs (aspirin and placebo) were packaged and donated by Meda Pharma. This analysis was supported by a VIDI innovative research grant from the Netherlands Organisation for Scientific Research (NWO) 016.126.364. There are no potential conflicts of interest to declare. This cohort study was nested in the randomized controlled trial; ALIFE study (Current Controlled Trials number, ISRCTN 58496168).
    Human Reproduction 03/2014; 29(6). DOI:10.1093/humrep/deu052 · 4.59 Impact Factor
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    ABSTRACT: Some recently emerged lipid-lowering therapies are currently restricted to patients with homozygous familial hypercholesterolemia (HoFH), and studies are underway to also assess these therapies in patients with ‘severe heterozygous FH (HeFH)’. However, no uniform definition of ‘severe HeFH’ exists, although untreated low-density lipoprotein cholesterol (LDL-C) levels above 8 mmol/L (309 mg/dl) have been historically used to define this phenotype. Our aim was to define severe HeFH, to establish its prevalence and CVD risk, and to study the relative contribution of classical risk factors to CVD risk in HeFH patients.
    Atherosclerosis 03/2014; 233(1). DOI:10.1016/j.atherosclerosis.2013.12.020 · 3.97 Impact Factor
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    ABSTRACT: Cardiovascular disease (CVD) remains the leading cause of death and morbidity in our society. One of the major risk factors for CVD is hypercholesterolemia. Hypercholesterolemia in children can be caused by a hereditary disorder or can be secondary to other diseases or drugs. In order to prevent CVD later in life, children with hypercholesterolemia should be identified and treated as early as possible. Currently, several different screening strategies have been developed, using either universal screening or case finding to search for children at risk. Once those children are identified, the first step in treatment is lifestyle adjustment. If cholesterol levels remain elevated, the drugs of first choice are statins. Other pharmacological options are ezetimibe or bile acid sequestrants. These agents have all proven to be safe and effective in lowering low-density lipoprotein cholesterol levels and improving surrogate markers of CVD. However, there is a need for long-term follow-up studies to answer the question as to whether it is safe to initiate treatment at a young age to prevent CVD later in life.
    Paediatric Drugs 01/2014; DOI:10.1007/s40272-013-0060-2 · 1.72 Impact Factor
  • D Meeike Kusters, Barbara Hutten
    Clinical Lipidology 12/2013; 8(6):611-613. DOI:10.2217/clp.13.70 · 0.86 Impact Factor

Publication Stats

5k Citations
1,145.55 Total Impact Points

Institutions

  • 2010–2015
    • Netherlands Bioinformatics Centre
      Nymegen, Gelderland, Netherlands
    • University of Queensland
      • Department of Medicine
      Brisbane, Queensland, Australia
  • 2000–2015
    • Academisch Medisch Centrum Universiteit van Amsterdam
      • • Department of Clinical Epidemiology and Biostatistics
      • • Academic Medical Center
      • • Department of Vascular Medicine
      • • Department of Internal Medicine
      Amsterdamo, North Holland, Netherlands
    • University of Amsterdam
      • • Department of Clinical Epidemiology and Biostatistics
      • • Faculty of Medicine AMC
      Amsterdamo, North Holland, Netherlands
  • 2009
    • AMC Health
      New York, New York, United States
  • 2006
    • Maastricht University
      Maestricht, Limburg, Netherlands
  • 2003
    • Erasmus MC
      Rotterdam, South Holland, Netherlands